Implant pellets and method using same

ABSTRACT

A system comprising a plurality of implantable pellets, wherein one such implantable pellet delivers localized, controlled and sustained release of a predetermined quantity of one or more pain relief agents, in optional combination with one or more anti-inflammatory agents, one or more polymeric excipients, and/or one or more surfactants. An anesthetic/analgesic pellet is used in combination with one or more pharmaceutical pellets as part of a single procedure to provide desired a pharmaceutical to the animal while simultaneously alleviating pain and, optionally, inflammation at the injection site.

CROSS-REFERENCE TO RELATED APPLICATIONS

This Application is a Divisional Application of the U.S. Utilityapplication having Ser. No. 10/381,864, now U.S. Pat. No. 7,767,218,which was a Section 371 National Stage filing from an InternationalApplication having International Publication No. WO 02/26179, whichclaimed priority from a U.S. Provisional Application having Ser. No.60/236,269.

FIELD OF THE INVENTION

The present invention is broadly concerned with a system comprising apellet implanting device, at least one pain relief pellet, and at leastone pharmaceutical pellet.

BACKGROUND OF THE INVENTION

Animal well-being and treatment are major concerns for animal welfaregroups and animal agriculturalists. Animal well-being and treatment arecontinual concerns because stressed or uncomfortable animals do notefficiently and profitably produce milk, meat, or eggs.

As those skilled in the art will appreciate, when tissue injury occurs,whether caused by bacteria, trauma, chemicals, heat, or any otherphenomenon, the body's inflammatory response is stimulated. In responseto signals released from the damaged cells (e.g., cytokines),extravascularization of immune effector cells is induced. Under ordinarycircumstances these invading immune effector cells kill the infectiousagent and/or infected or damaged cells (through the release of killingsubstances such as superoxides, performs, and other antimicrobial agentsstored in granules), remove the dead tissues and organisms (throughphagocytosis), release various biological response modifiers thatpromote rapid healing and covering of the wound (quite often resultingin the formation of fibrotic scar tissue), and then, after the area issuccessfully healed, exit from the site of the initial insult.

Once the site is perceived to be normal, the local release ofinflammatory cytokines ceases and the display of adhesion molecules onthe vessel endothelium returns to basal levels. In some cases, however,the zeal of these interacting signals and cellular systems, which aredesigned to capture and contain very rapidly multiplying infectiousagents, act to the detriment of the body, killing additional, otherwisehealthy, surrounding tissue. This additional unnecessary tissue deathfurther compromises organ function and sometimes results in death of theindividual.

SUMMARY OF THE INVENTION

A system comprising a plurality of implantable pellets is presented. Onesuch implantable pellet delivers localized, controlled and sustainedrelease of a predetermined quantity of one or more pain relief agents,in optional combination with one or more anti-inflammatory agents, oneor more polymeric excipients, and/or one or more surfactants.Applicants' anesthetic/analgesic pellet system is used in combinationwith one or more pharmaceutical implants as part of a single procedureto provide desired a pharmaceutical to the animal while simultaneouslyalleviating pain and, optionally, inflammation at the injection site.

Applicants' invention further includes a method for implantation ofsame. In certain embodiments, Applicants' method also includesimplantation of one or more pharmaceutical pellets in combination withimplantation of one or more pain relief/anti-inflammatory pellets,thereby providing localized, sustained, anesthetic/analgesic release atan injection site in order to reduce pain around the site of theinjection of the pharmaceutical pellets.

In certain embodiments, Applicants' method also includes implantation ofone or more anti-inflammatory pellets, thereby providing localized,sustained, anti-inflammatory release at an injection site in order toreduce inflammation around the site of the injection of the one or morepharmaceutical pellets.

Applicants' invention further comprises a pellet system which includesan implanter apparatus for subcutaneously injecting pharmaceuticalpellets into an animal through the bore of a hypodermic needle which isremotely coupled to a pellet magazine, and simultaneously implanting oneor more anesthetic/analgesic/anti-inflammatory pellets into theinjection site. Applicants' invention further includes a methodcomprising implantation of predetermined doses of one or morepharmaceutical pellets in combination with one or moreanesthetic/analgesic/anti-inflammatory agent(s) in a single injection.

Applicants' invention further comprises a method which permits anoperator to selectively implant an anesthetic/analgesic dose into ananimal, including humans. Applicants' invention further comprises amethod which permits serial injection of large numbers of animals in asingle session.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be better understood from a reading of the followingdetailed description taken in conjunction with the drawings in whichlike reference designators are used to designate like elements, and inwhich:

FIG. 1 is a fragmentary perspective view of an implantation apparatus ofuse when employing Applicants' method to relieve pain;

FIG. 2 is a fragmentary cross-sectional view showing Applicants'implantable pain relief pellets disposed within the implantationapparatus;

FIG. 3 is a fragmentary cross-sectional view showing implantation ofApplicants' pain relief pellets;

FIG. 4 recites Applicants' formulations A through S, wherein thoseformulations comprise one or more anesthetic agents in combination withone or more analgesic agents;

FIG. 5A recites Applicants' formulations AA through AS which include oneor more anesthetic agents in combination with one or more additionalingredients;

FIG. 5B recites Applicants' formulations AT through BL which include oneor more anesthetic agents in combination with one or more additionalingredients;

FIG. 6A recites Applicants' formulations CA through CS which include oneor more analgesic agents in combination with one or more additionalingredients;

FIG. 6B recites Applicants' formulations CT through DL which include oneor more analgesic agents in combination with one or more additionalingredients;

FIG. 7A recites Applicants' formulations EA through ES which include oneor more anesthetic agents in combination with one or more analgesicagents in combination with one or more additional ingredients; and

FIG. 7B recites Applicants' formulations ET through FL which include oneor more anesthetic agents in combination with one or more analgesicagents in combination with one or more additional ingredients.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

This invention is described in preferred embodiments in the followingdescription with reference to the Figures, in which like numbersrepresent the same or similar elements. Reference throughout thisspecification to “one embodiment,” “an embodiment,” or similar languagemeans that a particular feature, structure, or characteristic describedin connection with the embodiment is included in at least one embodimentof the present invention. Thus, appearances of the phrases “in oneembodiment,” “in an embodiment,” and similar language throughout thisspecification may, but do not necessarily, all refer to the sameembodiment.

The described features, structures, or characteristics of the inventionmay be combined in any suitable manner in one or more embodiments. Inthe following description, numerous specific details are recited toprovide a thorough understanding of embodiments of the invention. Oneskilled in the relevant art will recognize, however, that the inventionmay be practiced without one or more of the specific details, or withother methods, components, materials, and so forth. In other instances,well-known structures, materials, or operations are not shown ordescribed in detail to avoid obscuring aspects of the invention.

It is to be understood that the disclosed embodiments are merelyexemplary of the invention, which may be embodied in various forms.Therefore, specific structural, composition, and/or functional detailsdisclosed herein are not to be interpreted as limiting, but merely as abasis for the claims and as a representative basis for teaching oneskilled in the art to variously employ the present invention invirtually any appropriately detailed structure, composition, and/ormethod.

Applicants' invention comprises an implantable pellet comprising one ormore pain relief agents. By pain relief agent, Applicants mean one ormore anesthetic agents and/or one or more analgesic agents. Byanesthetic agent, Applicants mean a composition that induces a partialor total loss of the sense of pain, temperature, touch, and the like. Byanalgesic agent, Applicants mean a composition that induces a state ofnot being able to feel pain. Applicants' pain relief pellet can beformed by various methods including, but not limited to, compressionmolding and/or encapsulation.

In certain embodiments, Applicants' pain relief pellets comprise one ormore anesthetic agents, including those used in caudal, epidural,inhalation, injectable, retrobulbar, and spinal applications, such asbupivacaine, lidocaine, prilocaine, and mixtures thereof. In theseembodiments, the one or more anesthetic agents are present in an amountbetween about 5 weight percent and about 95 weight percent. FIGS. 5A and5B recite Applicants' formulations AA through BL which include one ormore anesthetic agents in combination with one or more additionalingredients discussed below.

In alternative embodiments, Applicants' pain relief pellets comprise oneor more analgesic agents, such as acetaminophen, ibuprofen, fluriprofen,ketoprofen, voltaren, phencetin, salicylamide, and mixtures thereof. Inthese embodiments, the one or more analgesic agents are present in anamount between about 5 weight percent and about 95 weight percent. FIGS.6A and 6B recite Applicants' formulations CA through DL which includeone or more analgesic agents in combination with one or more additionalingredients discussed below.

In yet other embodiments, Applicants' pain relief pellets comprise oneor more anesthetic agents in combination with one or more analgesicagents. In these embodiments, the one or more anesthetic agents incombination with the one or more analgesic agents are present in anaggregate amount between about 5 weight percent and about 95 weightpercent. FIG. 4 recites Applicants' formulations A through S, whereinthose formulations comprise one or more anesthetic agents in combinationwith one or more analgesic agents.

The weight percentages recited in FIG. 4 represent only theanesthetic/analgesic component of Applicants' pain relief formulation.In contrast, each formulation recited in FIGS. 7A and 7B includes one ofthe formulations recited in FIG. 4 in combination with one or moreadditional ingredients discussed below. For example, formulation EA(FIG. 7A) comprises an anesthetic agent(s)/analgesic agent(s) componentpresent at about 95 weight percent in combination with a surfactantcomponent present at about 5 weight percent. The anestheticagent(s)/analgesic agent(s) component of formulation EA includes any ofthe formulations recited in FIG. 4. Thus, formulation EA includes atabout a 95 weight percentage level, one or more of compositions AAthrough AS.

In certain embodiments, Applicants' implantable pellet also comprisesone or more anti-inflammatory agents. By anti-inflammatory agent,Applicants mean a composition that minimizes injury-produced vasculardilatation and the greatly increased blood flow associated therewith,and/or exudation of fluid from blood vessels into tissues withconcomitant swelling, and/or migration of leukocytes into the tissues,and/or gelation of fibrogen in intercellular spaces.

In certain embodiments, the one or more anti-inflammatory agents areselected from the group comprising, but not limited to, corticosteriods,keratolytics, and mixtures thereof. The one or more anti-inflammatoryagent components of Applicants' pain relief pellet are present in anamount up to about 90 weight percent.

Applicants' composition is formulated so as to be biodegradable in thetarget animals, including humans, and to control release of the activeingredients. In certain embodiments, Applicants' anesthetic compositionincludes one or more excipients, including but not limited to,polyethylene glycol, starch, dextran, polyvinylalcohol, poly2-ethyl-2-oxazoline, and mixtures thereof. In certain embodiments, suchexcipients are present in an amount at up to about 50 weight percent. Inother embodiments, such excipients are present in an amount betweenabout 5 weight percent and about 25 weight percent. In alternativeembodiments, such excipients are present in an amount between about 10weight percent and about 20 weight percent.

Poly-2-ethyl-2-oxazoline is a water-soluble polymeric material. As thoseskilled in the art will appreciate, poly 2-ethyl-2-oxazoline comprisessubstituted polyethyleneimine II. Polymer II can be formed by aring-opening polymerization of 2-ethyloxazoline I.

In certain embodiments, Applicants' implantable composition includespolymer II having a number average molecular weight of about 5,000, i.e.n equals about 50. This polymeric material is sold in commerce under thename AQUAZOL® 5 by Polymer Chemistry Innovations, Inc., 4231 SouthFremont, Tucson, Ariz. 85714. In other embodiments, Applicants'implantable composition includes polymer II having a number averagemolecular weight of about 50,000, i.e. n equals about 500. Thispolymeric material is sold in commerce under the name AQUAZOL® 50 byPolymer Chemistry Innovations, Inc. In alternative embodiments,Applicants' implantable composition includes polymer II having a numberaverage molecular weight of about 500,000, i.e. n equals about 5000.This polymeric material is sold in commerce under the name AQUAZOL® 500by Polymer Chemistry Innovations, Inc.

In certain embodiments, Applicants' pain relief pellets comprise one ormore surfactants. Such surfactants are selected from the groupconsisting of anionic surfactants, amphoteric surfactants, non-ionicsurfactants, and mixtures thereof. Certain embodiments of Applicants'pain relief pellet include one or more nonionic surfactants having aHydrophilic Lipophilic Balance (“HLB”) between about 5 and about 20.Such nonionic surfactants include polyoxyethylene/polyoxypropylene blockco-polymers, polyoxyethylene/alkyl ethers, polyoxyethylene sorbitanesters, and mixtures thereof. In certain embodiments, the surfactantcomponent of Applicants' implantable composition is present in an amountup to about 20 weight percent. In other embodiments, such one or moresurfactants are present in an amount between about 1 weight percent andabout 10 weight percent. In alternative embodiments, such one or moresurfactants are present in an amount between about 3 weight percent andabout 5 weight percent.

The rate of in vivo release from an implanted pellet comprising one ormore anesthetic agents, and/or one or more analgesic agents, and/or oneor more anti-inflammatory agents, and/or one or more pharmaceuticalcompositions, can be adjusted by: (i) varying the weight percentage ofone or more water soluble polymeric excipients, such as poly2-ethyl-2-oxazoline, and/or (ii) including a first surfactant andvarying the weight percentage of that first surfactant, (iii) includinga first surfactant at a first weight percentage level and a secondsurfactant at a second weight percentage level, and varying the ratiobetween said first weight percentage level and said second weightpercentage level, and/or (iv) including one or more non-ionicsurfactant(s) and varying the HLB(s) of those one or more non-ionicsurfactants. Thus, the inclusion of a water-soluble, polymeric excipientin combination with one or more surfactant allows the formulator toadjust the rate of time release of the anaesthetic agents/analgesicagents/anti-inflammatory agents comprising Applicants' implantablepellets. In addition, the rate of systemic delivery of one or morepharmaceutical compositions released from a pharmaceutical pelletimplanted in an animal and disposed adjacent one or more of Applicants'implantable pellets can be adjusted by: (i) including a first surfactantand varying the weight percentage of that first surfactant, (ii)including a first surfactant at a first weight percentage level and asecond surfactant at a second weight percentage level, and varying theratio between said first weight percentage level and said second weightpercentage level, and/or (iii) including one or more non-ionicsurfactant(s) and varying the HLB(s) of those one or more non-ionicsurfactants.

In certain embodiments, Applicants' pain relief pellet includes one ormore lubricants, including, for example, magnesium stearate and/orcroscarmellose sodium, especially as sold under the trademark Ac-Di-Sol®by FMC. Such lubricants are present in an amount up to about 5.0 weightpercent. Applicants' anesthetic composition may optionally also includea wide range of additives to facilitate application, to control release,to stabilize the composition and for other reasons well known in theart.

In certain embodiments, Applicants' method utilizes an implanter havinga pellet magazine in combination with an injection needle, as well asstructure permitting injection of pellets from the magazine through theneedle for implantation under the skin of an animal. In certainembodiments of Applicants' method, the magazine is loaded with painrelief pellets and pharmaceutical pellets for distribution in sequencesingly. In alternative embodiments, the magazine is loaded with painrelief pellets and pharmaceutical pellets for distribution in multiplesinto the same injection site.

Broadly speaking, the pellet system used in Applicants' method includesan implanter apparatus for subcutaneously implanting pharmaceuticalpellets in an animal through the bore of a hypodermic needle which isremotely coupled to a pellet magazine, and a plurality of pellets sizedto be implanted through the needle and positioned in the magazine forselective alignment of a pellet with the needle. In one embodiment, thepellets include one or more pharmaceutical doses, and at least one painrelief pellet. In certain embodiments, that pain relief pellet includesone or more anti-inflammatory agents. These various pellets are arrangedin the magazine in sequential order for simultaneous delivery of apharmaceutical dose and an anesthetic/analgesic/anti-inflammatory doseas part of a single injection.

Referring to FIG. 1, general the reference numeral 10 represents apellet implantation system in accordance with the invention. Theimplantation system 10 broadly includes a slide action implanterapparatus 12 which is used to implant solid form drugs orpharmaceuticals, such as pain relief pellets 40 (FIG. 2) andpharmaceutical pellets 42 (FIG. 2) from a magazine strip 16 into ananimal 30 through a hypodermic needle 18. The needle 18 is utilized byan operator 26 to create an opening 44 that produces an implantreceiving puncture 44 (FIG. 2) in the animal 30.

A suitable implanter apparatus 12 is illustrated and described in detailin U.S. Pat. No. 5,522,797, which is hereby incorporated herein, andgenerally includes a housing 20 having a grip 22 with a trigger assembly24 pivotally mounted therein. An impeller 17 is slidably mounted withinthe housing 20 in alignment with an interior bore 46 (FIG. 2) of theneedle 18 and aligned chambers 16 of the loaded pellet magazine strip14. The needle 18 is used to puncture through the skin or hide 32 of ananimal's ear 34, and the trigger 24 is squeezed toward the grip 22 ofthe housing 20 to initiate injection of the pellets 40 and 42 and so asto cause the impeller 17 to be urged through the magazine chamber 16 andneedle bore 46, thereby forcing the pellets 40 and 42 through the bore46 of needle 18 and into the puncture 44 in the ear 34.

Each magazine strip 14 of the implanter 12 typically contains multipleparallel aligned pellet doses stored in corresponding pellet chambers16, which are connected by interconnecting webs 28. The chambers 16 areslightly conical in shape and are arranged in a side-by-side parallelrelation. The chambers 16 may have internal frictional formations suchas beads or posts (not shown) to retain the pellets 40 and 42 thereinprior to insertion and which can be easily bypassed by application ofpressure to the trigger 24. A plurality of strips 14 can be connected inend-to-end relation to increase the implanting capacity before theimplanter 12 requires reloading. As the pellets 40 and 42 in anindividual magazine strip 14 are exhausted the empty strip 14 can bedetached from the remaining strips 14 located in the implanter 12 anddiscarded.

Each pellet chamber 16 is loaded with an arrangement of pellets 40 and42. The pellets 40 and 42 are composed of one or more activeingredients, either alone, formed into a pellet, in conjunction with oneor more excipients, formed as part of a polymeric based release systemsuch as co-extruded polymers or matrix polymer systems, or included aspart of a delivery system based on mass transfer through an opening or agel matrix, either by diffusion or osmotic pressure pumping of theactive ingredient.

Pellets 42 are formulated to include a pharmaceutical composition, suchas and without limitation, an antibiotic, insulin, endocrine hormones(such as growth and birth control hormones), a vaccine, a parasiticides,or other biocides. Thus in certain embodiments, one pellet 40 containsan anesthetic/analgesic composition/anti-inflammatory composition, andthe other pellet 42 contains one or more pharmaceutical compositions. Itis foreseen that the number of pellets for each group may vary or thatthe pain relief agent(s) and other non-pain relief pharmaceuticalcompositions may be mixed in one or more of the pellets 40.

Each magazine chamber 16 is prefilled with a preferred number ofdiscrete pellets 42, each containing a dose of one or morepharmaceutical compositions such as trenbolone acetate bovine growthhormone, along with at least one pellet 40 containing ananesthetic/analgesic/anti-inflammatory composition. The magazine strip14 is preferably loaded onto implanter housing 20 in an orientation sothat the pharmaceutical pellet 42 will be delivered first, followed bythe anesthetic pellet 40.

In use, an operator grasps the implanter 12 by the grip 22 and urges theneedle 18 into the hide 32 and under the skin of the target animal 30 tomake the implant-receiving puncture 44. The puncture 44 shown in FIG. 2is incomplete and the depth of the implant receiving puncture 44 shownin FIG. 2 is about half of the total depth as shown in FIG. 3. Theoperator 26 depresses the trigger member 24, thereby propelling a pin 50(FIG. 3) of the impeller member 17 forwardly through an aligned magazinechamber 16, forcing the pellets 40 and 42 through the needle bore 46 andinto the implant receiving puncture 44. The operator 26 then withdrawsthe needle 18, leaving the pellets 40 and 42 in the implant-receivingpuncture 44.

While the pharmaceuticals in pellet 42 are absorbed and utilizedsystemically by the animal 30, in one embodiment pellet 40 preferablydelivers most of its dose at the site of the implant receiving puncture44, although some of the anesthetic/analgesic/anti-inflammatory agent(s)may be absorbed and carried systemically. In this embodiment, pellet 40is preferably specifically formulated to deliver its dose locally ratherthan systemically, and at a controlled, predetermined rate over apreselected period of time. In another embodiment, pellet 40 isformulated to deliver a systemic anesthetic/analgesic/anti-inflammatorydose.

Those skilled in the art will appreciate that the magazine strip 14 maybe loaded for selective injection of more than one pain relief pellet40. Where a number of pharmaceutical pellets 42 are to be delivered, thepharmaceutical pellets may be sandwiched between two or more pain reliefpellets to provide localized anesthetic release at both ends of a longimplant receiving puncture 44. In other embodiments, pain relief pelletsare alternated with pharmaceutical composition pellets in a stack ofpellets for delivery throughout the implant-receiving puncture 44.

Applicants' implantable pain relief pellets, and method to relieve painusing same, may be employed efficaciously with cows, horses, sheep,swine, dogs, cats or any other suitable animal, including humans.

While the invention has been described in detail herein in accordancewith certain preferred embodiments thereof, many modifications andchanges therein my be effected by those skilled in the art. Accordingly,it is intended by the appended claims to cover all such modificationsand changes as fall within the true spirit and scope of the invention.

We claim:
 1. A method to reduce pain at the site of a subdermalimplantation of one or more pharmaceutical pellets, comprising:implanting in an animal a pharmaceutical pellet; and implanting in saidanimal a pain relief pellet comprising between about 5 weight percentand a about 95 weight percent of one or more pain relief agents andbetween about 3 weight percent to about 5 weight percent of one or moresurfactants, wherein said pain relief pellet is disposed adjacent saidpharmaceutical pellet.
 2. The method of claim 1, wherein said one ormore pain relief agents comprise one or more anesthetic agents.
 3. Themethod of claim 1, wherein said one or more pain relief agents compriseone or more analgesic agents.
 4. The method of claim 1, wherein said oneor more pain relief agents comprises one or more anesthetic agents andone or more analgesic agents.
 5. The method of claim 1, wherein saidimplanting in said animal a pain relief pellets comprises implanting apain relief pellet comprising one or more pain relief agents, one ormore surfactants, and one or more excipients in an amount up to about 50weight percent.
 6. The method of claim 5, wherein said one or moreexcipients comprise poly-2-ethyl-2-oxazoline having a number averagemolecular weight of about 5,000.
 7. The method of claim 1, wherein saidimplanting in said animal a pain relief pellet comprises implanting apain relief pellet comprising one or more pain relief agents and one ormore anti-inflammatory agents.
 8. The method of claim 1, wherein saidimplanting in said animal a pain relief pellets comprises implanting apain relief pellet comprising between about 5 weight percent and a about95 weight percent of one or more one or more anesthetic agents, betweenabout 5 weight percent and a about 95 weight percent of one or moreanalgesic agents, up to about 90 weight percent of one or moreanti-inflammatory agents, between about 3 weight percent to about 5weight percent of one or more surfactants, and one or more excipients inan amount up to about 50 weight percent.
 9. The method of claim 1,further comprising the steps of: providing an implantation apparatus;disposing in said implantation apparatus one or more pharmaceuticalpellets; disposing in said implantation apparatus one or more painrelief pellets; inserting said implantation apparatus through the skinof said animal; disposing in said animal said one or more pharmaceuticalpellets; disposing in said animal said one or more pain relief pellets;and removing said implantation apparatus from said animal.
 10. A methodto adjust the in vivo rate of release of one or more pain relief agentsfrom an implanted pellet, comprising the steps of: providing one or moreimplantable pellets comprising one or more pain relief agents incombination with a first surfactant, wherein said first surfactant ispresent at a first weight percentage; adjusting said first weightpercentage; and implanting in an animal said one or more implantablepellets.
 11. The method of claim 10, wherein said one or moreimplantable pellets further comprise a second surfactant, wherein saidsecond surfactant is present at a second weight percentage, furthercomprising the step of adjusting said second weight percentage.
 12. Themethod of claim 11, wherein said first surfactant comprises a firstnon-ionic surfactant having a first HLB and said second surfactantcomprises a second non-ionic surfactant having a second HLB.
 13. Themethod of claim 11, further comprising the step of adjusting the ratiobetween said first weight percentage and said second weight percentage.14. The method of claim 12, wherein said first surfactant comprises afirst non-ionic surfactant having a first HLB and said second surfactantcomprises a second non-ionic surfactant having a second HLB.
 15. Themethod of claim 10, wherein said implantable pellet further comprises awater soluble polymer, wherein said water soluble polymer is present ata third weight percentage, further comprising adjusting said thirdweight percentage.
 16. A method to adjust the delivery of one or morepharmaceutical compositions released from one or more implantedpharmaceutical pellets, comprising the steps of: providing one or morefirst implantable pellets comprising one or more pharmaceuticalcompositions; providing one or more second implantable pelletscomprising one or more pain relief compositions in combination with afirst surfactant, wherein said first surfactant is present at a firstweight percentage; adjusting said first weight percentage; implantingone or more of said first pellets in an animal; and implanting in saidanimal one or more of said second pellets, wherein at least one of saidone or more second pellets is disposed adjacent at least one of said oneor more first pellets.
 17. The method of claim 16, wherein said one ormore second pellets further comprise a second surfactant, wherein saidsecond surfactant is present at a second weight percentage, furthercomprising the step of adjusting said second weight percentage.
 18. Themethod of claim 17, wherein said first surfactant comprises a firstnon-ionic surfactant having a first HLB and said second surfactantcomprises a second non-ionic surfactant having a second HLB.
 19. Themethod of claim 17, further comprising the step of adjusting the ratiobetween said first weight percentage and said second weight percentage.20. The method of claim 19, wherein said first surfactant comprises afirst non-ionic surfactant having a first HLB and said second surfactantcomprises a second non-ionic surfactant having a second HLB.
 21. Themethod of claim 16, wherein said one or more second implantable pelletsfurther comprise a water soluble polymer, wherein said water solublepolymer is present at a third weight percentage, further comprising thestep of adjusting said third weight percentage.